6-substituted penicillanic acid and derivatives thereof

ABSTRACT

Disclosed herein are penicillanic acids and derivatives thereof which are substituted in the 6-position, processes for preparing such compounds and the utility thereof. The compounds of the invention have been found to be useful as antibacterial agents.

United States Patent [191 Dolfini et al.

[ Dec. 17, 1974 E. R. Squibb and Sons, Inc., Princeton, NJ. I

Filed: I Sept. 24, 1971 Appl. No.: 183,642

Assignee:

US. Cl 260/306.7 C, 260/2391, 424/271 Int. Cl C07d 99/14 Field of Search 260/306], 2391 References Cited OTHER PUBLICATIONS Nagarajan et al., Vol. 93:9, p. 2,3082,3l2. May 5. 1971.

Primary Examiner-Nicholas S. Rizzo Attorney, Agent, or Firm-Lawrence S. Levinson; Merle J. Smith; Stephen B. Davis 5 7 ABSTRACT Disclosed herein are penicillanic acids and derivatives. thereof which are substituted in the 6-position, processes for preparing such compounds and the utility thereof. The compounds of the invention have been found to be useful as antibacterial agents.

3 Claims, No Drawings 6-SI3BSTITUTED PENICILLANIC ACID AND DERIVATIVES THEREOF SUMMARY OF INVENTION This invention relates I to 6-substituted- 6- aminopeni'cillanic acid having the following Formula l:

wherein R is alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, alkoxy, acyloxy, cyano, halogen, aralkoxy, acyl,

arylthio, alkylthio, and alkyl having electronegative DESCRIPTION OF INVENTION This invention relates to novel 6-substituted-6-amino penicillanic acid and derivatives thereof which are active asantibacterial agents and are valuable intermediates utilized in the preparation of the acylated derivatives. The 6-substituted-6-aminopenicillanic acids and salts of this invention also possess antibacterial activity which is enhanced by acylation of the 6-amino group. ln Formula I above the term pharmaceutically acceptable cation means an alkali metal (e.g., sodium and potassium), an alkaline earth metal (e.g., calcium and magnesium), ammonium, or an amine, such as a lower alkyl amine (e.g., methylamine), a di(lower alkyl)amine (e.g., diethylamine), a phenyl-lower alkylamine (e.g.y benzylamine), a di(phenyl-lower alkyl)amine (e.g., dibenzylamine), or an alkylenediamine (e.g., N,- N'-dibenzylethylenediamine), or the like.

Compounds of formula I are prepared by reacting a Schiffs base of 6-amimopenicillanic acid of Formula ll:

wherein R is phenyl, X-substituted phenyl, lower alkyl or aralkyl (e.g., benzyl or phenethyl), wherein X is halogen (e.g., chloro, bromo), alkoxy, hydroxy, nitro,-

amine, or lower alkyl; with electrophilic reagent having the Formula lll:

lll

wherein L is leaving group such as halogen (e.g., chloro-, bromo-, andso forth), sulfonate, sulfate, methylsulfonyloxy, p-toluenesulfonyloxy, and R is as defined herein.

This reaction is conducted in the presence of a base, such as alkali metal hydroxide such as sodium hydroxide, potassium t-butoxide or sodium methoxide, or sodium hydride.

Compounds of Formula III that may be utilized in the practice of the invention are perchloryl fluoride, trifluoromethyl iodide, cyanogen chloride, acetyl chloride, benzoyl chloride, ethyl chloroformate, methylsulfenyl chloride, phenylsulfenyl chloride, chlorine, ethyl choroformate, methyl chloromethyl ether and so forth.

lt is to be understood that the term lower alkyl and lower alkoxy in the formulae of the instant invention include straight and branched chain radicals of from I to about 8 carbons such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, amyl, methoxy, ethoxy, propoxy, isopropoxy, and the like. Further, it will be appreciated that certain of the compounds of this invention exist in differentoptically activeforms. The various stereoisomeric forms as well as the racemic compounds are within the scope of this invention.

Suitable compounds of Formula II include any Schiffs base of 6-APA (or a protected form thereof). When using this process, the preferred Schiffs bases are those formed with aldehydes which do not interfere with the substitution reaction. Thus, although any of the Schiffs bases of 6-APA disclosed in U.S. Pat. No. 3,288,800 can be used, the preferred are those formed from aldehydes of the formula: RCl-lO, wherein R is phenyl, p-methoxyphenyl, m-nitrophenyl, halopenenyl and 0- (e.g.,- o-

(e.g., p-chlorophenyl, bromophenyl (lower m-fluorophenyl alkoxy)phenyl p-carbomethoxyphenyl, o-carboethoxyphenyl, p-carbohexyloxyphenyl, and m-carbobutoxyphenyl), o-npropoxyphenyl, and p-n-hexyloxyphenyl), di(lower alkyl) aminophenyl [e.g., p-dimethylaminophenyl, odiethylaminophenyl, o-diethylaminophenyl, p-(N-nbutyl-N-methylamino)-phenyl, and m-di-npentylaminophenyl], naphthyl. The reaction in forming compounds of Formula ll is preferably conducted in an inert organic solvent for the Schiffs base reactant, such as methylene chloride, benzene, dimethoxyethane, dioxane and chloroform.

Compounds of the Formula ll are preferably used in the form of an ester. Suitable esters include those formed with lower alkanols (e.g., methanol, ethanol and tert.-butanol), cycloalkanols (e.g., cyclohexanol and cyclopentanol), carbocyclic aryl alcohols (e.g., phenol and 2-naphthol), carbocyclic aryl (lower alkanols), e.g.,(benzyl alcohol, p-methoxybenzyl alcohol benzhydr'ol, l-naphthylmethyl alcohol and 2-phenylethanol), trimethylsilyl, lower alkanoyl (lower alkanols) (e.g., hydroxyacetone and pivaloylmethanol), carbocyclic aroyl(lower alkanols) (e.g., ben zoylmethanol, 2-benzoyletha'nol and 2naphthylcarbonylmethanol), cycloalkylcarbonyl(lower alkanols) (e.g., hyd-.

roxymethylcyclohexylketone), lower alkanoyloxy (lower alkanols) (e.g., pivaloyloxymethanol), and substituted derivatives of any of the above, such as lower thoxybenzhydrol, 2-dimethylamino ethanol, pnitrobenzoylmethanol and p-methoxybenzoylmethanol.

The reaction of Compound 11 with Compound III yields a compound of Formula IV:

in a cut which can then be converted to compounds of Formula I by hydrolysis in the presence of a mild aqueous acid, such as hydrochloric, sulfuric, formic, p-toluenesulphonic acid, trifluoroacetic and acetic acid to yield the -substituted-6-aminopenicillanic acid of Formula 1, preferably isolated as a salt.

As stated above compounds of Formula I are valuable intermediates in the formation of acylated compounds having the Formula V:

c. R CO where R contains from 2 to 7 carbon atoms and is alkenyl, alkylthioalkenyl, alkenylthioalkyl, alkoxyalkenyl or alkenyloxyalkyl,

d. R X,(Cl-l ),,CO- where R and n are as defined above and tisqx eu su ph e. R (CH2),.S(CH2),"CH2COwhere R and n are as defined above and m is O or an integer from 1 to 4.

f. R COwhere R is as defined above,

g. R (CH ),,CO where R is heterocyclic or subsituted heterocyclic (e.g., lower alkyl dihydrocyclohexyl, lower alkoxy dihydrocyclohexyl such as 2,4- dimethyl-Z,4-dihydrocyclohexyl, and 2-propoxy-2,4- dihydrocyclohexyl) and n is an integer from O, 1 to 4,

R! R (CH:)p--3HC0 where R is as defined herein, R is amino, ureido, car boxy, sulfonyl, phosphonyl, hydrogen. hydroxy, chloro, bromo, or iodo, p is an integer from O, 1 to 3, and

where R R and p are as defined above.

The formation of compounds of general Formula V may, for example, be effected by one of the following methods:

a. Reaction of the compound of general Formula 1 with an acid chloride, or acid anhydride, active ester, acid azide, etc, in aqueous or organic solution.

b. Reaction of the compound of general Formula I with a mixed anhydride of an acid corresponding to the desired acyl group and another acid, the mixed anhydride being formed by reaction of the acid corresponding to the desired acyl group with an alkyl haloformate, if desired formed in situ; the reaction with the mixed anhydride preferably being conducted in solution in an anhydrous, inert solvent in the presence of an acid binding agent e.g., a tertiary amine.

c. Reaction of the compound of Formula I with the activated form of a carboxylic acid formed by reaction with carbonyl-di-imidazole or dicyclohexylcarbodiimide or similar activating agent.

Acids, or functional derivatives thereof, which can be used to form derivatives of general Formula V include, in addition to the various acids corresponding to R, heterocyclic carboxylic acids e.g., nicotinic acid; substituted phosphorus acids e.g., dibenzylphosphorus acid; sulphonic acids (e.g., p-toluene sulphonic acid; and dicarboxylic acids.

The compounds of this invention have a broad spectrum of antibiotic activity. They have antibacterial activity against both gram-positive and gram-negative organisms, such as Staphylococcus aureus, Salmonella schottmuelleri, Pseudomonasaeruginosa, Proteus vulgaris, Escherichia coli and Streptococcus pyrogenes. They may be used as antibacterial agents in a prophylactic manner, e.g., in cleaning or disinfecting compositions, or otherwise to combat infections due to organisms such as those named above, and in general may be utilized in a manner similar to penicillin G and other pencillins. For example, a compound of Formula V may be used in various animal species in an amout of about 0.1 to mg/kg daily, orally or parenterally, in single or two to four divided doses to treat infections of bacterial origin. Up to about 600 mg. of a compound of Formula V may be incorporated in an oral dosage form such as tablets, capsules, or elixirs or an injectable form in a sterile aqueous vehicle prepared according to conventional pharmaceutical factors. The compounds of this invention also have lower allergenicity as compared to non-6-substituted penicillins. ln cleaning or disinfecting compositions, e.g., in farm or dairy equipment, a concentration of about 0.01 to 1% by weight of such compounds admixed with, suspended or dissolved in conventional inert dry or aqueous carriers by application by washing or spraying may be utilized.

The following examples illustrate the invention (all temperatures being in degrees Centigrade, unless otherwise stated):

EXAMPLE 1 N-Benzylidene-o-Aminopenicillanic Acid 73.8 Mmoles o-aminopenicillanic acid, t-octylamine salt is added to 240 ml. methylene chloride cooled to 0-5C. (water bath). After dispersion 158.5 mmoles benzaldehyde are added, followed by the addition of an 8 ml. tetrahydrofuran solution containing 76.2 mmoles trifluoroacetic acid. During the course of this addition, the reaction mixture gradually clarifies to finally form a clear, slightly yellow solution. The reaction mixture is allowed to reach room temperature and concentrated to one-third its volume in vacuo at a temperature not exceeding 30C. On cooling the desired product crystallized out in 82 mole EXAMPLE 2 a. Treatment of a 0.1 molar solution of N- benzylidene-6-aminopenicillanic acid with one equivalent of p-methoxy phenyl diazomethane in ether (Overberger and Anselme, J. ORG. CHEM., 28, 592 [1963]; Idem, .1. AM. CHEM. SOC., 86, 658 [1964]) for one hour, followed by evaporation deposits the product.

b. 0.1 equivalent N-salycilidene-6-aminopenicillanic acid in 400 ml dichloromethane is cooled to 3 5C and then treated with 0.1 equivalent pyridine and anisyl alcohol. This is followed by the addition of 0. 1 equivalent dicylohexylcarbodiimide in dichloromethane over V2 hour. The reaction temperature is then maintained between 3-5C for A2 hour, at room temperature for A hour and between 354 6C for one (1) hour. After cooling in ice for one hour the formed urea is filtered off. The filtrate is washed twice with water, once at pH 3.5 then at pH 7.5. The organic layer is separated, dried over'magnesium sulphate and evaporated to give, after crystallization 0.073 equivalent of N-salycilidene-6- aminopenicillanic acid, p-methoxy-benzyl ester. This is then treated with 1 equivalent p-toluenesulphonic acid and water in ethyl acetate for four hours. The formed p-toluenesulphonic acid salt of 6-aminopenicillanic acid, p-methoxy benzyl ester is then filtered off and treated with aqueous sodium bicarbonate to give 0.045

- EXAMPLE 3 Diphenylmethyl ester of aminopenicillanic acid V Substitution of one equivalent of diphenyldiazomethane for the solution of phenyl diazomethane in Example 2(a) gives the desired product.

N-benzylidene-6- EXAMPLE 4 Trichloroethyl ester of 6-benzaliminopenicillanic acid The Schiff base of Example 1 10.0 g) is dissolved in 150 ml of dichloromethane containing pyridine (5.2 g). Trichloroethanol (9.84 g) is added followed by 6.79 g dicyclohexylcarbodiimide and the mixture stirred for two hours at room temperature. Precipitation of dicyclohexylurea occurs quickly. After two hours the precipitate is filtered off. The filtrate is diluted with dichloromethane and washed twice with an equal volume of water, first at pH'3.5, then at pH 7.2. It is then washed with saturated sodium chloride, dried over anhydrous magnesium sulfate, and stripped to dryness in vacuo. Wt. of yellow oil 15.6 g.

The product is crystallizedby dissolving it in 5 ml of ether and adding hexane to the warm solution until slightly turbid upon cooling.

EXAMPLE 5 Methyl ester of 6-benzaliminopenicillanic acid By treating a dioxane solution of the product of Example l with excess ethereal diazomethane, followed by evaporation of the solvent, the desired product is obtained. Trituration with hexane gives a powder.

6 EXAMPLE 6 6-Benzalimino-6-cyanopenicillanic methoxybenzyl ester A solution of mg. of 6-benzalimino-penicillanic acid, p-methoxybenzyl ester, in 5 ml. of dimethoxyethane was treated with 35 mg of potassium t-butoxide at l0C under an argon atmosphere. After stirring for 5 minutes a solution of 20 mg of cyanogen chloride in l ml dimethoxy ethane was added. After stirring for 30 minutes the reaction mix was poured into pH 4.6 buffer and layered with ethyl acetate. The organic layer was washed with water and brine then dried (Na SO and evaporated to deposit the product.

EXAMPLE 7 acid, p-

-Benzalimino-6-ethoxycarbonyl penicillanic acid,

p-methoxybenzl ester By following the procedure of Example 6, but substituting a solution of 78 mg of ethylchloroformate in 1 ml dimethoxy ethane in place of the ClCN the desired product is obtained.

EXAMPLE 8 6-Benzalimino-6-fluoropenicillanic methoxybenzyl ester By following the procedure of Example 6, but substituting 1 ml DME containing 38 mg of fluorylperchlorate for the ClCN solution, the desired product is obtained.

acid, p-

EXAMPLE 9 EXAMPLE 10' 6-Benzalimino-6-acetylpenicillanic acid, p-

methoxybenzyl ester. 12.5 Meq. 6-benzalimino-penicillanic acid, p-

methoxybenzyl ester are dissolved in 2 ml. dry DME under nitrogen at -5C. Then 12.5 meq. potassium tbutoxide is added. The reaction mixture turns yellow after a few minutes of stirring at that low temperature.

Then a 20 fold excess acetyl chloride is added. After 3 hours, thin layer chromatography on silica gel, showed no more starting material. The reaction mixture is diluted with chloroform washed with water, dried over magnesium sulphate and evaporated in vacuo to give the product.

EXAMPLE 10A 6-Benzalimino-6lmethylthiopenicillanic methoxybenzyl ester. 7 v A solution of -methylthiopenicillanic mg of 6-benacid, p-

zalirnino-penicilTa riic acid, p m tlioxyb enzyl ester in 5 ml of dimethoxyethane was treated with 37 mg potassium t-butoxide at -30C under nitrogen atmosphere. After stirring for 3 minutes, 27 mg methylsulfenyl chloride was added, and stirring was continued for two minutes. The reaction was poured into cold pH 4.6 buffer and layered with ethyl acetate. The organic layer was washed with water,'dried (Na SO and evaporated at reduced pressure to deposit the product.

EXAMPLE 1 l 6-Benzalimino-6-acetylpenicillanic acid, methyl ester Substitution of 12.5 meq. of the methyl ester of 6- benzyliminopenicillanic acid in Example 10 for the pmethoxybenzyl ester leads to the desired product.

EXAMPLE 12 6-Benzalimino-6-acetylpenicillanic acid, benzhydryl ester By substituting 12.5 meq. of the benzhydryl ester for the p-methoxybenzyl ester of Example 10, the desired product is obtained.

EXAMPLE 13 6-Amino-6-acetylpenicillanic acid, p-methoxybenzyl ester a. 5.1 Meq. 6-benza1imino-o-acetylpenicillanic acid, p-methoxybenzyl ester are hydrolyzed in a 50:50 mixture of acetone and 0.1 N aqueous hydrochloric acid for 10 minutes. The reaction mixture is then diluted with water and washed with chloroform. The acidic layer is then basified and extracted with chloroform. This latter chloroform layer is dried over magnesium sulphate and evaporated to dryness in vacuo to give -6-amino--acetylpenicillanic acid, p-methoxybenzyl ester.

b. 4.5 Meq. 6-benzalimino-6-acetylpenicillanic acid, p-methoxybenzyl ester are dissolved in ethyl acetate and treated with 5.5 meq. p-toluenesulphoric acid and water for 4 hours. The formed solid is removed by filtration and shaken between aqueous bicarbonate and dichloromethane. The'organic layer is dried over magnesium sulphate and evaporated to dryness to give 2.7 meq. of the desired compound.

EXAMPLE 13A 6-Amino-o-methylthiopenicillanic methoxybenzyl ester. Substituting the product of Example 10A for the substrate in Example 13, and following the procedure therein, the desired product is obtained.

EXAMPLE 14 6-Amino-o-acetylpenicillanic acid methyl ester Substituting 5.l meq of the product of Example 11 acid, p-

for the substrate of Example 13, and following the procedure therein, the desired product is obtained.

, EXAMPLE 15 6-Amino-6-acetylpenicillanic acid, benzhydryl ester Substituting 5.1 meq. of the product of Example 12 for the substrate of Example 13, and following the procedure therein, the desired product is obtained.

EXAMPLE 15A 6-Amino-6-acetyl penicillanic acid,

A solution of 100 mg of the 6-amino-6-acetyl penicillanic acid, p-methoxybenzyl ester in 15 ml water acidified to pH 2 by HCl is stirred at room temperature for 3 hours. The solution is extracted three times with 10 ml ether, then lyophylized to deposit the hydrochloride of the desired product.

EXAMPLE 16 6-Phenylacetamido-6-p-nitrophenyl thiopenicillanic acid, p-methoxybenzyl ester A solution of 1.51 meq. of 6-benzalimino-6-pnitrophenylsulfenyl sulfenyl penicillanic acid, pmethoxybenzyl ester in 10 ml. methyl isobutyl ketone is treated with 1.51 meq. of phenylacetyl chloride with ice bath cooling. One ml. of water and 1.51 meq. of triethylamine is then added. After 30 minutes the mixture is diluted with 50 ml. of ethyl acetate. The organic solution is washed with dilute aqueous bicarbonate solution followed by water and pH 4.6 buffer. It is dried (Na S0 and evaporated to give the product.

EXAMPLE 1 6A 6-Phenylacetamido-6-fluoropenicillanic methoxybenzyl ester By substituting product of Example 8 for 6- benzalimino-6-p-nitrophenyl-penicillanic acid, pmethoxybenzyl ester in Example 16 the desired product was obtained.

acid, p-

EXAMPLE 17 acid, p-

EXAMPLE 17A 6-Phenylacetamido-tS-methylthiopenicillanic p-methoxybenzyl ester 1. By substituting the product of Example 10A for 6- benzalimino-6-p-nitrophenylsulfenylpenicillanic acid, p-methoxybenzyl ester in Example 16 the desired product was obtained.

2. By substituting the product of Example 13A for acid,

'6-amino-6-acety1penicillanic acid, p-methoxybenzyl ester in Example 17, the desired product fell out.

EXAMPLE 18 6-Phenylacetamido-6-methoxycarbonylpenicillanic acid, p-methoxybenzyl ester v Substitution of 2.25 meq. 6-amino-6-methoxycarbonylpenicillanic acid, p-methoxybenzyl ester, (prepared by using methylchloroformate in place of the cyanogen chloride in Example 6 followed by hydrolysis as in Example 13, for 6-amino-6-acetylpenicillanic acid, p-methoxybenzyl ester) in Example 17 yields the desired product.

EXAMPLE 19 6-Phenylacetamido-6-acetylpenici1lanic acid oxane: ml. Water. 10 grams 10% Pd/CaCO are added and the mixture is treated with hydrogen until gas uptake ceases. The catalyst is then removed by filtration and the desired free acid is isolated in 69% yield.

b. By hydrolysis: A solution of 5 g. of the pmethoxybenzyl ester in 30 ml of 5:1 dioxane water is acidified to pH2with hydrochloric acid, after 1.5 hours, the solution is diluted with water, the pH adjusted to 7-8, and extracted with ether. The aqueous is then acidified and the product extorted into ether. The ether solution is washed (H O), dried (N SO and evaporated to deposit the product EXAMPLE 6-Phenylacetamido-6-p-nitrophenyl-thiopenicillanic acid. By substituting 6-phenylacetamido-6-pnitrophenylsulfenylpenicillanic acid, p-methoxybenzyl ester for 6-phenylacetamido-6-acetylpenicillanic acid, p-methoxybenzyl ester in Example 19, the desired product is obtained.

EXAMPLE 21 6-Ben2a]imino-6-trifluoromethylpenicillanic acid,

p-methoxybenzyl ester 6-Benzalimino-6-trifluoromethylpenicillani acid,

p-methoxybenzyl ester is prepared by using trifluoromethyl iodide in lieu of acetyl chloride of Example 10.

EXAMPLE 22 EXAMPLE 22A 6-Phenylacetamido-6-trifluromethylpenicillanic acid, p-methoxybenzyl ester. B y substituting product of Example 22 for 6-amino-6-acetylpenicillanic acid, p-methoxybenzyl ester in Example 13, the desired product was obtained.

EXAMPLE 22B 6-Phenylacetamido--fluoropenicillanic acid.

6-Phenylacetamido-6-fluoropenicillanic acid is prepared by Example 19, substituting the corresponding fluoro compound for the acetyl compound.

EXAMPLE 23 6-Amino-6-cyanopenicillanic acid, p-methoxybenzy] ester 6- Amino-6-cyanopenicillanic acid, p-methoxybenzyl ester is prepared by using the product of Example 6 to replace the substrate 6-acetyl compound of Example 13.

EXAMPLE 24 6-Phenylacetamido-o-cyanopenicillanic methoxybenzyl ester 7 acid, p-

6-Phenylacetamido--cyanopenicillanic acid,, pmethoxybenzyl ester is prepared by using the product of Example 23 for the substrate in Example 1?.

EXAMPLE 25 6-Phenylacetamido-6-cyanopenicillanic acid 6-Phenylacetamido-6-cyanopenicillanic acid is prepared by the Example 19, substituting the corresponding cyano compound for the acetyl compound.

EXAMPLE 25A EXAMPLE 25B 6-Phenylacetamido-6-methylthiopenicillanic acid 6-Phenylacetamido-6-methylthiopenicillanic acid is prepared by Example 19, substituting the correspond ing methylthio compound for the acetyl compound.

EXAMPLE 26-48 6-Acylamino-6-acetylpenicillanic acids By following the procedure of Example 17 and substituting an equivalent amount of the corresponding acid chloride of the following carboxylic acids 'a-(2-chlorophenoxy )propionic acid, a-(4-sulfamylphenoxy)-n-butyric acid, a-(3,4-dimethoxyphenoxy)-n-pentanoic acid, a-(3-methylphenoxy)isovaleric acid, a-(4-methylthiophenoxy)propionic acid, a-(4-dimethylamimophenoxy)-n-hexanoic acid, a-(2-methoxyphenoxy)-n-decanoic acid, a-(2,4-dichlorophenoxy)phenylacetic acid, a-(2-ni trophenoxy)-B-phenylpropionic acid, a(2-acetamidophenoxy)- -phenylbut yric acid, a-(2,4-dimethylphenoxy)-n-butyric acid, a-(4-isopropylphenoxy)propionic acid, oz-(3-bromophenoxy)-n-butyric acid, a-(2-iodophenoxy)phenylacetic acid, a-(Z-diethylaminophenoxy)isovaleric acid, a-( 3,5-dichlorophenoxy)isohexanoic acid, a-(4-cyclohexylphenoxy)propionic acid, a-phenoxy-isovaleric acid, a-phenoxy-n-decanoic acid, oz-phenoxy- -phenylbutyric acid, a-(2-benzylphenoxy)-n-butyric acid, a-(2-trifluoromethylphenoxy)propionic acid, and a-(4-fluorophenoxy)propionic acid, the products are obtained after following the procedure of Example 19,

6-[a-(2-chlorophenoxy)propionamido]-6- acetylpenicillanic acid, 6-[a-(4-sulfamylphenoxy)-n-butyramido]-6- acetylpenicillanic acid, 6-[a-( 3,4-dimethoxyphenoxy )-n-pentano amido]-6- acetylpenicillanic acid, 6-[a-(3-methylphenoxy)isovaleramido]-6-' acetylpenicillanic acid, 6-[a-(4-methylthiophenoxy)propionamido]-6- acetylpenicillanic acid, 6-[a-(4-dimethylaminophenoxy)rn-hexanoamido]-6- acetylpenicillanic acid,

6-[ oz-( Z-methoxyphenoxy)n-decanoamido1-6- acetylpenicillanic acid, I

6-[a-(2,4-dichlorophenoxy )phenylacetamido1-6- acetylpenicillanic acid,

6-[oz-(2-nitrophenoxy)-B-phenylpropionamido]-6- acetylpenicillanic acid,

6-[a(Z-acetamidophenoxy)-B-phenylbutyramido]- 6-acetylpenicillanic acid,

6-[a-(2,4-dimethylphenoxy)-n-butyramido]-6- acetylpenicillanic acid,

6-[a-(4-isopropylphenoxy)propionamido1-6- acetylpenicillanic acid,

6-[a-(3-bromophenoxy)-n-butyramido]-6- acetylpenicillanic acid,

6-[0l-(2-iodophen0xy)phenylacetamido1-6- acetylpenicillanic acid,

6-[a-(2-diethylaminophenoxy)isovaleramido1-6- acetylpenicillanic acid,

6-[a-( 3,5-dichlorophenoxy )isohxanoamido1-6- acetylpenicillanic acid,

' 6-[a-(4-cyclohexylphenoxy)propionamido1-6- acetylpenicillanic acid,

6-[a-(phenoxy-isovaleramido]-6-acetylpenicillanic acid,

6-[a-phenoxy-n-decanoamido]-6-acetylpenicillanic acid,

6-[a-phenoxy-2-phenylbutyramido1-6- acetylpenicillanic acid,

6-[a-(Z-benzylphenoxy)-n-butyramido]-6- acetylpenicillanic acid,

6-[01-( Z-trifluoromethylphenoxy)propionamido1-6- acetylpenicillanic acid, and

(i-[ a-(4-fluorophcnoxy)propionamido1-6- :icctylpenicillanic acid, respectively.

EXAMPLES 4978 By following the procedure of Example 24 and sub stituting an equivalent amount of the corresponding acid chloride of the following carboxylic acids a-phenylthiopropionic acid, a-paranitrophenylthiopropionic acid, a-parachlorophenylthiopropionic acid, a-phenylthiobutyric acid, a-phenylthiocaproic acid, u-phenylthioisovaleric acid. 01-(4-tbutylphenylthio)propionic acid, a-ortho-tolyIthiopropionic acid, a-ortho-nitrophenylthiopropionic acid, a-parachlorophenylthiobutyric acid, a-(3,4,5-trichlorophenylthio)propionic acid, a-( 3-trifluoromethylphenylthio)butyric acid, a-parabromophenylthioisovaleric acid, a-paraphenylphenylthiopropionic acid, a-(4-methoxyphenylthio)caproic acid, a-(4-cyclohexylphenylthio)butyric acid, a-phenylthio-a-cyclohexylacetic acid, a-phenyIthio-a-cyclopentylacetic acid, a-(2,4-dichlorophenylthio)caproic acid, a-( 2,4-diisoamylphenylthio)propionic acid, a-(4-benzylphenylthio)propionic acid, a-(4-sulfamylphenylthio )butyric acid, a-(2-allyloxyphenylthio)propionic acid, a-( 4-allylphenylthio)isovaleric acid, a-(4-dimethylaminophenylthio)propionic acid, a-(2,S-dichlorophenylthio)butyric acid, a-( 2-iodophenylthio)propionic acid, a-(2-acetamidophenylthio)propionic acid,

a-(4-diethylaminophcnylthio)propionic acid, and a-(3-flu0rophenylthio)butyric acid,

the products are obtained after following the procedure of Example 25,

6-(a-phenylthiopropionamido)-6-cyanopenicillanic acid, 6-(oz-paranitrophenylthiopropionamido)-6- cyanopenicillanic acid, 6-(oz-parachlorophenylthiopropionamido )-6- cyanopenicillanic acid, 6-(a-phenylthiobutyramido)-6-cyanopenicillanic acid, 6-(a-phenylthiocaproamido)-6-cyanopenicillanic acid, 6-(oz-phenylthioisougleramida)-6-cyanopenicillanic acid, 6-[a-(4-t-butylphenylthio)propionamido1-6- cyanopenicillanic acid,

v6-[oz-ortho-tolylthiopropionamido]-6- cyanopenicillanic acid, 6-(a-ortho-nitrophenylthiopropionamido)-6- cyanopencillanic acid, 6-(a-parachlorophenylthiobutyramido)-6- cyanopenicillanic acid, 6-[a-(3,45-trichlorophenylthio)propionamido1-6- V cyanopenicillanic acid, 6-[0z-( 3-trifluoromethylphenylthio)butyramido1-6- cyanopenicillanic acid, 6-(a-parabromophenylthioisovaleramido)-6- cyanopenicillanic acid, 6-( a-paraphenylphenylthiopropionamido )6- cyanopenicillanic acid, 6-{a-(4-methoxyphenylthio)caproamido1-6- cyanopenicillanic acid, 6-[a-(4-cyclohcxylphenylthio)butyramidol-ocyanopenicillanic acid, 6-(a-phenylthio-a-cyclohexylacetamido)-6- cyanopenicillanic acid, 6-(a-phenylthio-a cyclopentylacetamido)-6- cyanopenicillanic acid, 6[a-( 2,4-dichlorophenylthio )caproamido ]-6- cyanopenicillanic acid, 6-[a-(2,4-diisoamylphcnylthio)propionamido1-6- cyanopenicillanic acid, 6-[a-(4-benzylphcnylthio)propionamido1-6- cyanopenicillanic acid, 6-[a-(4-sulfamylphenylthio)butyramido]-6- cyanopenicillanic acid, 6-[a-(2-allyloxyphenylthio)propionamido1-6- cyanopencillanic acid,

.6[a-(4-allylphenylthio)isovaleramido1-6- EXAMPLES 79-92 By following the procedure of Example 16A and substituting an equivalent amount of the corresponding the products are obtained after following the procedure of Example 22,

D,L-6-[a-amino-(3-thienyl)acetamido1-6- fluoropenicillanic acid, 6-[a-amino-( -ethyl-2-thienyl )acetamidol-ofluoropenicillanic acid, 6-[a-amino-(S-methyI-Z-thienyl)acetamido1-6- fluoropenicillanic acid, 6-[-amino-(S-t-buty])-2-thienyl)acetamido1-6- fluoropenicillanic acid, 6-[a-amino-(2,5-dimethyl-3-thienyl)acetamido]-6- fluoropenicillanic acid, 6- a-amino-( 5-chloro-2-thienyl )acetamido1-6- fluoropenicillanic acid, 6-[a-amino-(S-brorno-Z-thienyl)acetamido1-6- fluoropenicill'anic acid, (1-[a-amino-(5:phenyl-3-chloro-2- thienyhacetamidol-o-fluoropenicillanic acid, b-{ a-aminod 3 ,S-dimcthyl-Z-thienyl )acetamido 1-6- fluoropenicillanic acid, 6-[a-amino-(5-cyclohexyl-2-thienyl)acetamidol-ofluoropenicillanic acid, 6-[a-amino-(5-diethylamino-2-thienyl)acetamidolo-fluoropenicillanic acid, 6-[a-amino-(4-methylsulfonyI-2-thienyl)acetamidol- 6-fluoropenicillanic acid, 6-[o1-amino-(3-ethylthio-2-thienyl)ac'etamidol-ofluoropenicillanic acid, and 6-[a-amino-(4-cycloheptyloxy-2- I thienyl)acetamido1-6-fluoropenicillanic acid, respectively.

EXAMPLES 93-115 By following the procedure of Example 18 and substituting an equivalent amount of the corresponding acid chloride of the following carboxylic acids a-amino-p-chlorophenylacetic acid, a-amino-p-methoxyphenylacetic acid, L-(+)-a-aminophenylacetic acid, a-amino-4-diethylaminophenylacetic acid, a-amino-4-trifluoromethylphenylacetic acid, a-amino-2,4-dibromophenylacetic acid, a-amino-Z-nitrophenylacetic acid, a-amino-3-methylphenylacetic acid, a-amino-4-sulfamylphenylacetic acid, a-amino-Z-iodophenylacetic acid, oz-amino-4-t-butylphenylacetic acid, a-amino-2-acetamidophenylacetic acid, a-amino-3nitrophenylacetic acid, u-amino-3,4-dimethoxyphcnylacetic acid, a-amino-4-dimcthylaminophenylacctic acid,

14 a-amino-Z,4-dichlorophenylacetic acid, a-amino-4-isopropylphenylacetic acid, a-amino-3-bromophenylacetic acid, a-amino-3-iodophenylacetic acid,

5 a-amino-Z-diethylaminophenylacetic acid',

oz-amino-2-trifluoromethylphenylacetic acid, a-amino-4-fluorophenylacetic-acid, and oz-amino- 3,4,5-trifluoromethylphenylacetic acid,

the products are obtained by following the procedure of Example 25A are,

6-(a-amino-p-chlorophenylacetamido)-6- methoxycarbonylpenicillanic acid, 6-(a-amino-p-methoxyphenylacetamido)-6- methoxycarbonylpenicillanic acid 6-[L-(+)-a-aminophenylacetamido]-6-methoxycarbonylpenicillanic acid, 6-(a-amino-4-diethylaminophenylacetamido)-6- methoxycarbonylpenicillanic acid, 6(a-amino-4-trifluoromethylphenylacetamido)-6- Q methoxycarbonylpenicillanic acid,

6-(a-amino2,4-dibromophenylacetamido )-6- methoxycarbonylpenicillanic acid, 6-(a-amino-Z-nitrophenylac etamido)-6-mcthoxycarbonylpenicillanic acid, 6-(a-amino-3-methylphenylacetamido)-6 methoxycarbonylpenicillanic acid, 6-(a-amino-4-sulfamylphenylacetamido )-6- methoxycarbonylpencillanic acid, 6-(a-amino-2-iodophenylacetamido)-6-methoxycar- 3O bonylpenicillanic acid,

6-(a-amin0-4-t-butylphenylacetamido)-6- methoxycarbonylpenicillanic acid, 6-(a-amino-2-acetamidophenylacetamido)-6- methoxycarbonylpenicillanic acid, 6-(a-amino-3-nitrophenylacetamido)-6-mcthoxycarbonylpenicillanic acid, 6-(a-amino-3,4-dimethoxyphenylacetamido)-6- methoxycarbonylpenicillanic acid, '6-(a-amino-4-dimethylaminophenylacetamido)-6- methoxycarbonylpenicillanic acid,

6-(oz-amino-2,4-dichlorophenylacetamido)-6- methoxycarbonylpenicillanic acid, 6-(a-amino-4-isopropylphenylacetamido)-6- methoxycarbonylpenicillanic acid, 6-(a-amino-3-bromophenylacetamido)-6- methoxycarbonylpenicillanic acid, 6-(oi-aminc-3-iodopheny]acetamido)-6-methoxycarbonylpenicillanic acid, 5O 6-(a-amino-2-diethylaminophenylacetamido) 6- methoxycarbonylpenicillanic acid, 6-(a-amino-2-trifluoromethylphenylacetamido)-6- methoxycarbonylpenicillanic acid, 6-(a-amino-4-fluorophenylacetamido)-6- methoxycarbonylpenicillanic acid,

6-(a-amino-3,45-trifluoromethylphenylacetamido 6-methoxycarbonylpenicillanic'acid,

. EXAMPLES Il6-l85 By following the procedure of Example 17 and substituting an equivalent amount of the following acid chloride of the 3,5-dinitrobenzoyl chloride,

2-chlorobenzoyl chloride,

Z-methylbenzoyl chloride,

4-aminobenzoyl chloride,

4-nitrohcnzoyl chloride,

4-hydmxyhcnzoyl chloride,

3,4,5-trimethoxybenzoyl chloride, 4-methylbenzoyl chloride, 4-chlorobenzoyl chloride, 3,4-dichlorobenzoyl chloride,

2,6-diallyloxybenzoyl chloride, 3-bromo-2,-diethoxybenzoyl chloride, 4-chloro-2,(i-dimethoxybenzoyl chloride, 2-chloro-6-nitrobenzoyl chloride, and 2-hydroxy-6-methoxybenzoyl chloride,

6(2-chlorobenzamido)-6-acetylpenicillanic acid, 6-( Z-methylbenzamido)-6-acetylpenicillanic acid, 6-(4-aminobenzamido)-6-acetylpenicillanic acid, 6-(4-nitrobenzamido)-6-acetylpenicillanic acid,

3-nitrobenzoyl chloride, 5 6-(4-hydroxybenzamido)-6-acetylpenicillanic acid, methoxybenzoyl chloride, 6 (3,45-trimethoxybenzamido)-6-acetylpenicillanic 2-hydroxybenzoyl chloride, acid, 4-ethoxybenzoyl Chloride, 6-(4-methylbenzamido)-6-acetylpenicillanic acid, 2,6- im hoxybenzoyl c O dfi. 6-(4-chlorobenzamido)-6-acetylpenicillanic acid, y y chloride, 10 6-(3,4-dichlorobenzamido)-6-acetylpenicillanic 2,6-dichlorobenzoyl chloride, id ,6-di y y Chloride; 6-(3-nitrobenzamido)-6-acetylpenicillzmic acid, ly y Chkmde- 6-(2,46-trimethoxybenzamido)-6-acetylpcnicillz1nic 2,6-dibenzyloxybenzoyl chloride, acid, 'l $y chlflridea 6-(2-hydroxybenzamido)-6-methylpenicillanic acid, m y ChlQTldff, 6-(4-ethoxybenzamido)-6-acetylpenicillanic acid, zr6'df'n'propoxybenzwl chlonde, 6-(2,6-dimethoxybenzamido)-6-acetylpenicillanic 2,6-d1methoxy-4-methylbenzoyl chloride, acid 46'dlethyl-z-methoxybenzoyl ChlSmdE, 6-(2,46-trimethylbenzamido)-6-acetylpenicillanic 6-ethoxy-2-methoxybenzoyl chloride, acid z'methymllobenzcyl chlorlde 6-(2,6-dichlorobenzamido)-6-acetylpenicillanic 2-benzylth1obenzoyl chloride, acid Z'PhenOXybenZOyI f 6-(2,6-diethoxybenzamido)-6-acetylpenicillanic Z-phenylbenzoyl chloride, acid z'met-hoxybgnzoyl chlorlde 6-(2,6-di-n-butoxybenzamido)-6-acetylpenicillanic 4-sulfamylbenzoyl chloride, acid 3 Adlmethoxybenzoyl m 6-( 2,6-dibenzyloxybenzamido )-6-acetylpenicillanic 4-methoxybenzoyl chloride, acid 3-methylbenzoyl chloride, 3 dimethylaminobenzoyl chloride, -giigb-trlmethoxybenzamido)-6 acetylpeniclllamc Z-methoxybenzoyl chloride, I LChIOmJAitrimethowbenzoy} chloride 62.2,g6-trlbormobcnzamido)-6-acetylpemc1llamc 2,4-dichlorobenzoyl chloride, l zmitmbenzoyl chloride. 6{125g-di-n-propoxybenzam1do)-6-acetylpen1cillamc 4-methylaminobenzoyl chloride, Z-acetamidobenZOYl chloride, 22::g i gggggggigz y 2,4-dimethylben2oyl chloride, 2,4,5-trimethylbenzoyl chloride, -ggi gi s i fiz gggy 4-isopropylbenzoyl chloride, 3 3 bmmobenzoyl Chloride 40 6-(6-ethoxy:2 -methox fbenzamido)-6- 2-iodobenzoyl chloride, acetylpemclllamc q z ethylaminobenzoyl chloride 6-(2 methylthiobenzamido)-6-acetylpemcillamc 2,5-dihydroxybenzoyl chloride, acid 4 hydmxy 3 methoxybenzoyl Chloride 6-(Z Zfil'lZYlIhlObfiflZQlTlldO)-6-8C6Iylp6nlClllaIllC 4-all lbenzo lchloride, 4 auloxybeizoyl chloride, 6-(Z-phenoxybenzarnido)-6-acetylpenicillanic acid, ltrifluoromethylbenzoyl Chloride, 6-(2 phenylbenzamido)-6-acetylpemcillamc acid, 4 fluorobenzoyl chloride 6-(Z-methoxybenzamido)-6-acetylpenicillan ic acid, z phenylthiobenzoyl chloride 6-(4-sulfamylbenzamido)-6-acetylpen1cillamc acid, 2 benZy1benZ-Oy| Chloride, 6-(3,4-dimethoxybenzamido) 6-acetylpenicillanic 2,6-dihydroxybenzoyl chloride, acid 2,6-diacetoxybenzoyl chloride, 6-(4-methoxybenzamido)-6-acetylpenicillamc acid, 2(ydimethylthiobenzoyl Chloride, 6-(3-methylbenzamido)-6-acetylpenicillanic acid, 2,4b4rinitmbenzoy] chloride, 6-(3:dimethylaminobenzamido)-6-acetylpenicillanic 2,o-diacetamidobenzoyl chloride, 161d, 2,6-dibrOmObenZOy] chlorids, 6-(Z-methoxybenzamido)-6-acetylpenicillanic acid, 2,6-dimethylbenzoyl chloride, 6-(2-chloro-3,4,5-trimethoxybenzamido)-6- 2,6-diethylbenzoyl chloride, acetylpenicmanic 361d, 2,6-diisoprop lbenzo l chlo id 6-(2,4-dichlorobenzamido)-6-acetylpenicillanic acid, 6-(2-nitrobenzamido)-6-acetylpenicillanic acid, 6-(4-methylaminobenzamido )-6-acetylpenicillanic acid, 6-( Z-acetamid'obenzamido)-6-acetylpenicillanic acid, 6-( 2,4-dimethylbenzamido)-6-acetylpenicillanic acid,

the products obtained are, following the procedure of Example 19,

6-(3,5-dinitrobenzamido)-6-acetylpenicillanic acid,

acid,

6-(4-is opropylbenzamido)-6-acetylpenicillanic acid,

6-( 3-bromobenzamido)-6-acetylpenicillanic acid, 6-(2-iodobenzamido)-6-acetylpenicillanic acid, 6-(2-ethylaminobenzamido)-6-acetylpenicillanic acid, 6-(2,5-dihydroxybenzamido)-6-acetylpenicillanic acid, 6-(4-hydroxy-3-methoxybenzamido)-6- acetylpenicillanic acid, 6-(4-allylbenzamido)-6-acetylpenicillanic acid, 6-(4-allyloxybenzamido)-6-acetylpenicillanic acid, 6-(2-tribluoromethylbenzamido)-6- acetylpenicillanic acid, 7 6-(4-fluorobenzamido)-6-acetylpenicillanic acid, 6-(2-phenylthiobenzamido)-6-acetylpenicillanic acid, 6-( 2-benzylbenzamido)-6-acetylpenicillanic acid, 6-( 2,6 dihydroxybenzamido )-6-acetylpenicillanic acid, 6-(2,6-diacetoxybenzamido)-6 acetylpenicillanic acid, 6-(2,o-dimethylthiobenzamido)-6-acetylpenicillanic acid, I 6-( 2 ,46-trinitrobenzamido )-6-acetylpenicillanic acid, 7 6-( 2,6-diacetamidobenzamido )-6-acetylpenicillanic acid, 1 6-('2,6-dibromobenzamido)-6-acetylpenicillanic acid, 6-(2.6dimethylbenzamido)-6-acetylpenicillanic acid, 6-( 2,6-diethylbenzamido)-6-acetylpenicillanic acid, 6-(2,o-diisopropylbenzamido)-6-acetylpenicillanic acid. 6-(2,6-diallyloxybenzamido)-6-acetylpenicillanic acid, 6-( 3-bromo-2,6-diemthoxybenzamido)-6- acetylpenicillanic acid,

6-( 4 chloro-2,6-dimethoxybenzamido )-6- acetylpenicillanic acid. 6-(2-chloro-o-nitrobenzamido)-6-acetylpenicillariic acid, and 6-( 2-hydroxy-b-methoxybenzamido)-6- acetylpenicillanic acid, respectively.

EXAMPLE l86-l96 By following the procedure of Example 16 and substituting an equivalent amount of the corresponding acid chloride of the following carboxylic acids (4-nitrophenyl)acetyl chloride, (4-bromophenyl)acetyl chloride,

(4-t-butylphenyl)acetyl chloride,

(4-tribluoromethylphenyl)acetyl chloride, (3-fluorophenyl)acetyl chloride, (4-sulfamylphenyl)acetyl chloride, (2-benzylphenyl)acetyl chloride, (3-methoxyphenyl)acetyl chloride, (2-iodophenyl)acetyl chloride, (3-diethylaminophenyl)acetyl chloride, and

. '(2,4-diisoamylphenyl)acetyl chloride.

the products are obtained by following the procedure of Example 20:

6'[ oz-( 4.-nitrophenyl )acetamido l-b-nitrophenylthiopenicillanic acid.

18 6-[a-(4-bromophenyl)acetarnido]'-6-nitrophenylthiopenicillanic acid, 6-[a-(4-t-butylpehnyl)acetamido]-6-nitrophenylthiopenicillanic acid, 7 6- a-( 4-trifluoromethylphenyl )acetamido-6- nitrophenylthiopenicillanic acid, 6-[a-( 3-fluorophenyl)acetamido]-6-nitrophenylthiopenicillanic acid, 6-[a-(4-sulfamylphenyl)acetamido]-6-nitrophenyll0 thiopenicillanic acid,

6[a-( 2-benzylphenyl )acetamidol-6-nitrophcnylthiopenicillanic acid, 6-[a-(3-methoxyphenyl)acetamidol-o-nitrophcnylthiopenicillanic acid, 6 [a-(2-ioodphenyl)acetamidol-6-nitrophenylthiopenicillanic acid, 6[0z-(3-diethylaminophenyl)acetamido1-6- nitrophenylthiopenicillanic acid, and 6-[a-(2,4-diisoamylphenyl)acetamido1-6- nitrophenylthiopenicillanic acid, respectively.

EXAMPLES .197-243 By following the procedure of Example 17A and substituting an equivalent amount of the following acid chloride 3-m-chlorophenyl-5-methyl 4-isoxazole-4-carbonyl chloride, 3-(3,4-dichlor0phenyl)-5-methyl-4-isoXazole-4- carbonyl chloride, 3-p-tolyl-5-methyl-4-isoxazole-4 carbonyl chloride,

3-0-nitrophenyl-S-methyl-4-isoxazole-4-carbonyl chloride, 3-m-nitrophenyl-5-methyl-4-isoxazole-4-carbonyl chloride, 3-p-nitrophenyl-5-methyl-4-isoxazole-4-carb0nyl chloride, 3-p-bromophenyl-5-methyl-4-isoxazole-4-carbonyl chloride, 3-p-fluorophenyl-5-methyl-4-isoxazole-4-carbonyl 40 chloride,

3-p-methylsulfo'nylphenyl-S-methyl-4-isoxazole-4- carbonyl chloride, 3-p-methoxyphenyl-5-methyl-4-isoxazole-4-carbonyl chloride, 3-p-trifluoromethylphenyl-5-methyl-4-isoxazole-4- carbonyl chloride, 3-o-methoxyphenyl-5-methyl-4-isoxazole-4-carbonyl chloride, 5O 3-p-ethoxyphenyl-5-methyl-4-isoxazole-4-carbonyl chloride, 3-(3,4-dimethoxyphenyl)-5-methyl-4-isoxazole-4- carbonyl chloride, 3p-dimethylaminophenyl-5-methyl4-isoxazole-4- carbonyl chloride,

3-oz-naphthyl-5-methyl-4is'oxazole-4-carbonyl chloride, 3-B-naphthyl-4-methyl-4-isoxazole-4-carbonyl chloride, 3-phenyl 5-ethyl-4-isoxazole-4-carbonyl chloride,

3-p-chlorophenyl-5-ethyl-4-isoxazole-4-carbonyl chloride, -3-phenyl-5-isopropyl-4-isoxazole-4-carbonyl chloride, 6S 3-phenyl-5-methylmercapto-4-isoxazole-4-carbonyl chloride,

3-methyl-5-o-chlorophenyl-4-isoxazole-4-carbonyl chloride,

21 butyl-S-methyl-4-isoxazolyl-6-methylthiopenicillanic acid, 3-methyl-5-p-trifluoromethylphenyl-4-isoxazolyl-6- methylthiopenicillanic acid, 3-methyl-5-cyclohexyl-4-isoxazolyl-6-methylthiopenicillanic acid, 3-cyclohexyl-5-methyl-4-isoxazolyl-6-methylthiopenicillanic acid, 3-a-furyl-5-methyl-4-isoXazolyl-6-methylthiopenicillanic acid, and 3-a-thienyl-5methyl-4risoxazolyL-methylthiopenicillanic acid, respectively.

EXAMPLE 244258 By following the procedure of Example 17A and sub- 3-tert.

stituting an equivalent amount of the following acid chloride 3,5-diphenyl-4-isoxazole-4-carbonyl chloride, 3-methyl-5-phenyl4-isoxazole-4-carbonyl chloride, 3,5-dimethyl-4-isoxazole-4-carbonyl chloride,

5-benzyl-3-methyl-4-isoxazole-4-carbonyl chloride,

3 methyl-S-styryl-4-isoxazole-4-carbonyl chloride,

ride, 3-methyl-5-(3',5'-dirnethyl-4'-isoxazolyl)-4- isoxazole-4-carb0nyl chloride, 3-methyl-5-(Z-thienyl)-4-isoxazole-4-carbonyl chloride, 3-(p'chlorophenyl)-5-methyl-4-isoxazole-4-carbonyl chloride. 3-methyl-5 methylmercapto-4-isoxazole-4-carbonyl chloride, 5-(p-chlorophenyl)-3-methyl-4-isoxazole-4-carb0nyl chloride, 3-methyl-5-(o-nitrophenyl)-4-isoxazoIe-4-carbonyl chloride, v 5-isopropyl-3-methyl-4-isoxazole-4-carbonyl ride, and 5-mcthyl-3-(p-chlorophenyl)-4-isoxazole-4'carb0nyl chloride, the products obtained by following the procedures of Example 258 are 3,5-diphenyl-4-isoxazolyl-6-methylthiopenicillanic acid, I 3-methyl-5-phenyl-4-isoxazolyl-6-methylthiopenicillanic acid, 3,5dimethyl-4-isoxazolyI-o-methylthiopenicillanic acid, 5-ben2yl- 3-methyl-4-isoxazolyl--methylthiopenicillanic acid, 3-methyl-5-styry1-4-isoxazolyl-o-mcthylthiopenicillanic acid. S-tert. butyl-3-phenyl-4-isoxazolyl-6-methylthiopenicillanic acid, 5-(2-furyl)e3-methyl-4-isoxazolyl-6 methylthiopenicillanic acid, 3-methyl-5-(3',5'-dimethyl-4'-isoxazolyl)-4- isoxazolyl-6-methylthiopenicillanic acid, 3-methyl 5-(2-thienyl)-4-isoxazolyl-6-methylthiopenicillanic acid, 3-(p-chlorophenyl)-5-methyl-4-isoxazolyl-6-methylthiopenicillanic acid, 3-methyl-5-m'ethylmercapto-4-isoxazolyl-6-rnethylthiopenicillanic acid, 5-(p-chlorophenyl)-3-methyl-4-isoxazolyl-6-methylthiopenicillanic acid,

chlo- 3-methyl-5-( o-nitrophenyl)-4-isoxazolyl-6-methylthiopenicillanic acid, 5-isopropyl-3-methyl-4-isoxazolyl-6 methylthiopenicillanic acid,- 5 5-methyl-3-( p-chlorophenyl)-4-isoxazolyl-6-methylthiopenicillanic acid, repsectively.

EXAMPLES 259-272 By following the procedure of Example 24 and sub- 10 stituting an equivalent amount of the following acid chloride a-(3-thienyl)glycyl chloride, a-( 5-ethyl-2-thienyl)glycyl chloride, a-(S-methyl-Z-thienyl)glycyl chloride, a-(5-t-butyl-2-thienyl)glycyl chloride, a-(2,5-dimethyl-3-thienyl)glycyl chloride. a-(5-chloro-2-thienyl )glycyl chloride, a-( S-b'romo-Z-thienyl)glycyl chloride, a-(5-phenyl-3-chloro-2-thienyl)glycyl chloride, a-( 3,5-dimethyl-2-thienyl)glycyl chloride, a-(5-cyclohexyl-2-thienyl)glycyl chloride, a-(5-diethylamino-2-thienyl)glycyl chloride, a-(4methylsulfony]-2-thieny])glycyl chloride, a-( 3-ethylthio-2-thienyl)glycyl chloride, and a-(4-cycloheptyloxy-2thienyl)glycyl Y chloride, re-

spectively. the products obtained by following the procedure of Example 25 are D,L-6-[a-amino-(3-thienyl)acetamido]-6- cyanopenicillanic acid, 6-[a-amino(S-ethyl-Z-thienyl)acetamido]-6- cyanopenicillanic acid, 6-[a-amino(5-methyl-2-thienyl)acetamido]-6 cyanopenicillanic acid, 6-[oz-amino(5-t-butyl-2-thienyl)acetamido1-6- cyanopenicillanic acid, 6-[a-amino-2,5-dimethyl-3-thienyl)acetamido1-6- cyanopenicillanic acid, ,6-[ a-amino-(5-chloro-2 thienyl)acetamido1-6 cyanopenicillanic acid, 6-[a -amino-(S-bromo-Z-thienyl)acetarnidol-6- cyanopenicillanic acid, 6-[a-amino-(5-phenyl-3-chloro-2- thienyl)acetamido]-6-cyanopenicillanic acid, 6-[a-amin0-(3,5-dimethyl-2-thienyl)acetamido1-6- cyanopenicillanic acid, 6-[a-amino-(5-cyclohexyl-2-thienyl)acetamido1-6- cyanopenicillanic acid, v 6-[a-amino-( S-diethylamino-Z-thieny)acetamido1-6 cyanopenicillanic acid, 6-[a-amino-(4-methylsulfonyl-2-thienyl)acetamidol- 6-cyanopenicillanic acid, 6-[a-amino-( 3-ethylthio-2-thienyl )acetamido]-6- cyanopenicillanic acid, and 5 6-[a-amino-(4-cycloheptyloxy-2- thienyl)acetamido]'6 -cyanopenicillanic acid, respectively.

EXAMPLE 273 6-Amino-6-methoxymethyl penicillanic acid A solution of 0.1 mole of N-benzylidene-6-amino penicilla'nic acid in mlof dimethoxy ethane is treated with 0.05 mole of bic-trimethylsilyl acetamide at 0C. After 30 minutes an equivalent of sodium hydride is added, followed 15 minutes later by 0.1 mole of methyl chloromethyl ether. After 1 hour the solution of 6-benzalimino-6-methoxymethylpenicillanic acid, trimethylsilyl ester is hydrolyzed by adding 100 ml water and adjusting to pH2. The solution is extracted with ethyl acetate and the pH readjusted to 4.5 to 5. Concentration of the aqueous deposits 6-amino-6- methoxymethylpenicillanic acid.

EXAMPLE 274 6-Amino-6-carbolthoxymethylpenicillanic acid By substituting 0.1 ml of ethyl bromoacetate for the methyl chloromethyl ether of the Example 273, the desired product is obtained.

EXAMPLE 275 6-(Z-Thienylacetamido)-6-methoxymethylpenicillanic acid A solution of 1 mmol of the product of Example 292 in 10 ml 121 aqueous acetone is treated with 1 mmol of 2-thienylacetyl chloride at C. A solution of triethylamine in acetone is added to maintain a pH at 7.5. When no further pH change is noted, the reaction is extracted with ether. Acidification of the aqueous yields the desired free acid. What is claimed is: l. A compound having the formula:

C; S HQN T O= COOR methoxybenzyl ester.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION PATENTNO. 3 55 233 DATED Dec. 17, 1974 INVENTOMS): J. E. Dolfini, Ekkehard Bohme, and W. A. Slusarchyk ItBcemfiedmatmmrmmemsn1meamwe-memfiwdpmmnamthmsmdLefiasPamm mehmdwcmmcmdasdwwnbdow Col. 1, line 45, "6-amimopenicillanic" should read 6aminopenicillanic.

Col. 2, line 55, "2naphthylcarbonylme-" should read 2-naphthylcarbonylme- Col. 5, line 10, "N-salycilidene" should read Nsalicilidene.

Col. 6, line 17, "p-methoxybenzl" should read p-methoxybenzyl-.

Col. 6, line 37, "2.34" should read 2.35.

Col. 6, line 62, "6lmethylthiopenicillanic" should read 6-methylthiopenicillanic-.

Col. 6, line 64, "methylthiopenicillanic" should be deleted and -l4l should be inserted in its place.

Col. 8, line 22, "nitrophenyl-penicillanic" should read nitrophenylsulfenylpenicillanic-.

Col. 10, line 14, "metoxycarbonylpenicillanic" should read methoxycarbonylpenicillanic.

Col. 10, line 36, "dimethylamimophenoxy" should read dimethylaminophenoxy.

Col. 10, line 40, "a(2-acetamidophenoxy) should read a-(2-acetamidophenoxy)y UNITED STATES PATENT OFFICE CERTEF'ICATE OFF CORRECTION Page 2 Pawn NO. 3 ,s55,233

- omen Dec. 17 1974 WVEYTORKS J. E. Dolfini, E. Bohme, and W. A. Slusarchyk H is candied that error ace-ears above-ldentified patent sa d LEiZEiS Patent ar csrl'ectari as shown below,

Col. 10, line 50, "phenoxyshould read phenoxyy Col. 11, line 1, "methoxyphenoxy)n" should read methoxyphenoxy) n- Col 12, line 15, "phenylthioisougleramida" should read phenylthioisovaleramido.

Col. 12, line 41, "6[o" should read -6-[d--.

Col 12, line 51 "6 [01" should read -6[cx-.

C61. 13, line 9, delete "pl".

' Col. 13 line 10, insert "'OL-- before "amino" Col. 13, line 11, delete "93-".

Col. 13 line 25, "6[-amino" should read 6- [ci.amino.

Col l4 line 19 "6 (01" should read '--6-'(OL-.

Col l8 line 11 "6 [01" should read --6--[oe--.

Col. 18, line 17 "6 [01" should read 6[cx.

Col. 18, line 53, "3p" should read -3p-.

Col. 20, line 50, "isoxazolyll6" should read -isoxaZolyl6-. Col.- 22, line 48, "2-thieny) should read 2thienyl)-.

Col 23, line 15, "292" should read 273.

Signed and Scaled this twenty-third D ay 0f September 1975 [SEAL] A ttes t:

RUTH C. MASON C. MARSHALL DANN A M-fli g jfit ('mnmm'imu'r ufluu'nts uml Trademarks Notice of Adverse Decision in Interference In Interference No. 99,126, involving Patent No. 3,855,233, J. E. Dolfini, E. Bohme and W. A. Slusarchyk, G-SUBSTITUTED PENICILLANIC ACID AND DERIVATIVES THEREOF, final judgment adverse to the patentees was renderer Aug. 2, 1976, as to claims 1, 2 and 3. [Oyficz'al Gazette November 30, 1976.] 

1. A COMPOUND HAVING THE FORMULA:
 2. A compound in accordance with claim 1 wherein R3 is methylthio.
 3. A compound in accordance with claim 2 having the name 6-amino-6-methylthiopenicillanic acid, p-methoxybenzyl ester. 